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HDL Hypothesis: Where Do We Stand Now?

  • Nonstatin Drugs (WB Borden, Section Editor)
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Abstract

There is robust epidemiological evidence dating back to the original Framingham Heart Study from 1977 that indicates an important inverse relationship between high-density lipoprotein cholesterol (HDL-C) and risk of incident coronary artery disease (CAD). Despite this body of scientific information demonstrating that low levels of HDL-C are an independent predictor of subsequent CAD events, multiple therapeutic attempts to raise HDL-C levels have failed to demonstrate a consistent reduction in prognostically important endpoints such as death, myocardial infarction (MI), and stroke. Recently, several major randomized trials using different therapeutic interventions have raised appropriate concerns about our basic understanding of HDL-C and whether the “HDL hypothesis” of lowering cardiovascular events through therapeutic interventions directed at raising HDL-C is a scientifically viable one. While two recent randomized controlled trials (AIM-HIGH and HPS2-THRIVE) failed to show a reduction in cardiovascular events in patients treated to optimally low levels of low-density lipoprotein cholesterol (LDL-C) at baseline with extended-release niacin on a background of simvastatin, these clinical trials studied specific populations of stable ischemic heart disease patients. The data from these two contemporary trials cannot be extrapolated to all patient populations, such as those with acute coronary syndromes or myocardial infarction or those with significant residual mixed dyslipidemia not treated with optimal doses of intensive statin therapy, as these patients were excluded by trial design in both studies. Therefore, at the present time, there is insufficient evidence from clinical trials to recommend HDL-targeted therapy for additional event reduction in CAD patients. However, we will review the relevant data from recent major trials (AIM-HIGH, HPS2-THRIVE, ILLUMINATE, and dal-OUTCOMES) and highlight the potential clinical implications of these trials in modern pharmacotherapy as it relates to HDL-C raising and potential cardiovascular event reduction.

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Conflict of Interest

Sayed M. Tariq, Mandeep S. Sidhu, and William E. Boden declare that they have no conflict of interest.

Peter P. Toth is a consultant to Amgen, Atherotech, Kowa, Liposcience, Merck, and Novartis; received payment for development of educational presentations from Amarin, Genzyme, GSK, Kowa, and Merck.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Department of Medicine, Albany Medical Center, Albany Medical College, Albany, NY, USA

    Sayed M. Tariq

  2. Department of Medicine, Albany Stratton VA Medical Center and Albany Medical Center, Albany Medical College, 113 Holland Avenue, Albany, NY, 12208, USA

    Mandeep S. Sidhu & William E. Boden

  3. Department of Family and Community Medicine, University of Illinois School of Medicine, and CGH Medical Center, Sterling, IL, USA

    Peter P. Toth

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  1. Sayed M. Tariq
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  2. Mandeep S. Sidhu
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Correspondence to William E. Boden.

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Tariq, S.M., Sidhu, M.S., Toth, P.P. et al. HDL Hypothesis: Where Do We Stand Now?. Curr Atheroscler Rep 16, 398 (2014). https://doi.org/10.1007/s11883-014-0398-0

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